A drug currently under investigation as an Alzheimer’s treatment may show promise for Parkinson’s disease as well, suggests a paper in the October 11 ACS Chemical Neuroscience. Bexarotene, an approved cancer drug, made headlines in 2012 when researchers claimed it cleared Aβ plaques and improved cognition in mice modeling AD (see ARF related news story). Subsequent attempts to independently reproduce these original findings have met with mixed success (see ARF related news story). Now a new group joins the fray, reporting that bexarotene protects dopaminergic neurons and improves movement in models of Parkinson’s. What’s more, the drug seems to work differently than AD researchers had envisaged. Scientists led by Ethan Burstein of Acadia Pharmaceuticals in San Diego, California, report that the drug activates a nuclear hormone receptor called Nurr1, known to promote growth and survival of dopamine neurons. Curiously, much lower doses are needed for these effects than are typically used for cancer treatment. The authors suggest the drug could one day be used to treat PD.

Bexarotene binds the retinoic acid receptor heterodimers RXR-PPARγ and RXR-LXR, upregulating expression of ApoE. “It seems that bexarotene can also work through Nurr1 to elicit these robust neuroprotective effects,” said Gary Landreth, Case Western Reserve University, Cleveland, Ohio, who originally put the drug on the map for AD. “We and everyone else have focused on astrocyte-driven ApoE production or the microglial inflammatory reaction,” he said.

Nurr1 shields dopaminergic neurons from neurotoxicity, regulates genes needed for their trophic support, and limits brain inflammation. Mutations in the Nurr1 gene also associate with PD (see PDGene entry). Scientists have reasoned in principle that a Nurr1 activator could help treat Parkinson’s, but Nurr1 itself has no known natural agonists. It does, however, form complexes with other nuclear hormone receptors, such as RXR, suggesting that agonists of these partner receptors may indirectly modulate Nurr1 action.

To find such compounds, first author Krista McFarland and colleagues screened a library of small molecules, looking for those that interact specifically with Nurr1 complexes. The scientists found that bexarotene activated Nurr1-RXR complexes better than it did RXR homodimers. Since bexarotene is FDA-approved for use in humans, they pursued it as a potential PD therapy.

They first tested the drug in a 6-hydroxydopamine (6-OHDA)-based rat model of PD. Within three days this chemical destroyed half the dopamine neurons in the substantia nigra pars compacta, a site of neuron loss in PD. For 28 days, the researchers then administered bexarotene into the brain, under the skin, or orally. Each of these treatments prevented the motor deficits usually seen in this model, and restored the number of dopaminergic neurons to normal (see image below). Bexarotene-treated rats performed as well as wild-type controls in a cognitive test as well, outsmarting the 6-OHDA-lesioned animals in a novel object recognition task.

image

Reprinted with permission from McFarland et al., 2013. 2013 American Chemical Society.

The effects were dose-dependent and the drug seemed potent. As little as 1 milligram per kilogram per day delivered orally had pronounced effects, versus the 100 mg/kg/day used in rat cancer studies. “I am completely blown away by the effect sizes and the remarkable dose dependency,” Landreth told Alzforum. The average cancer patient takes about 650 mg (about 8.0 mg/kg) of bexarotene per day, a dose typically associated with side effects such as rising cholesterol and hyperthyroidism. Based on these rat studies, however, the authors estimate that PD patients would need less than a tenth of that dose (about 10–60 milligrams per day) to see benefits. Lower doses produced fewer side effects in rats, and would likely be safer in humans as well, wrote the authors.

The cognitive boosting power of low-dose bexarotene in PD models suggests that similar amounts could rescue cognition in other neurodegenerative diseases, said Rada Koldamova, University of Pittsburgh, Pennsylvania. “This study tells me we should try lower doses in our experiments with AD mouse models,” she said. It is unknown whether such small amounts would clear Aβ, she noted.

Part of the bexarotene controversy surrounds the way the drug was prepared. According to Landreth, McFarland and colleagues used the same oral formulation of bexarotene he used in the original AD mouse study; that is, suspension in oil or water and administration by gavage. This maintains the microcrystalline structure of the drug. Landreth contends that recent attempts to replicate his data fell short because researchers chose different formulations of the drug.

Interestingly, the low doses of bexarotene used in the current study bumped up expression of ApoE and ABCA1, an effect Landreth previously reported using 100-fold higher doses. Landreth said he is steadily reducing the bexarotene dose in further experiments, but has not yet gone as low as 1 mg/kg. He recently initiated a Phase 1b study of bexarotene in 12 young, healthy volunteers to examine bexarotene’s effect on Aβ production and clearance. A separate Phase 2 trial is currently underway at the Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas.—Gwyneth Dickey Zakaib

References:
McFarland K, Spalding TA, Hubbard D, Ma JN, Olsson R, Burstein ES.Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease. ACS Chem Neurosci. 2013 Oct 11 [Epub ahead of print] Abstract

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  1. The positive effects of bexarotene treatment observed by McFarland and coworkers in the 6-hydroxydopamine Parkinson’s mouse model add to a growing body of literature that suggest pharmacological targeting of nuclear hormone receptors (NHRs), including RXRs, LXRs, and PPARs, may be beneficial in neurodegenerative diseases. Of particular interest was the fact that chronic bexarotene administration inhibited the loss of tyrosine hydroxylase-positive neurons in response to 6-OHDA challenge. This is the first report of bexarotene exerting neuroprotective effects rather than altering the clearance of proteins associated with neurodegenerative disease, such as Aβ. While the mechanism by which NHR agonists exert beneficial effects is undoubtedly complex, an intriguing component may be modulation of microglial activation in the brain. In the MPTP model of Parkinson’s disease, Dai and coworkers implicated microglial LXRβ activation as being neuroprotective of dopaminergic neurons (Dai et al., 2012). In regard to Alzheimer’s disease, Michael Heneka’s group reported that agonists of PPAR-γ increased microglial phagocytosis and degradation of soluble Aβ in vitro and in vivo (Yamanaka et al., 2012. Gary Landreth’s group reported similar effects of pioglitazone treatment and also noted that pioglitazone shifted the activation state from pro-inflammatory M1 to a more phagocytic M2 state Mandrekar-Colucci et al., 2012. It will be interesting to know whether the effects observed by McFarland and coworkers are also dependent upon microglia function. It is important to underscore that transgenic or pharmacological mouse models of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, while useful tools, do not recapitulate the human disease. Therefore, it is critical to develop biomarkers that can validate whether NHR-regulated pathways are also relevant in the setting of the human disease.

    View all comments by Gerald Ulrich
  2. This is a very exciting paper discussing the role of Rexinoid X Receptor (RXR) agonists in the treatment of Parkinson’s disease. Overall, at least from a conceptual point of view, McFarland et al. provide confirmatory evidence for the mechanistic role of RXR agonists in protecting the dopaminergic system.

    Interestingly, in this study the investigators show that the compound may have equivalent efficacious doses lower than those that are currently used in the treatment of T-cell lymphoma. The paper would have greatly benefited from presenting more evidence of binding affinity of bexarotene for activation of Nurr1, as well as evidence that bexarotene does or does not transactivate other RXRs, including RAR, fXR, lXR, PPRγ. Bexarotene affinity for these receptors may play an important role in its efficacy and side effects. This should have been reported in this manuscript, since this issue is a major hurdle in the clinical development of RXR agonists.

    We also note that Dr. Bjorklund (personal communication) found that bexarotene increases expression of the Liver X Receptor-dependent genes ApoE and ABCA1 in the model presented by McFarland. This is interesting since Dr. Gary Landreth’s group showed that bexarotene, delivered at 100mg/kg, cleared Aβ through upregulation of ApoE. Despite the present authors concluding that neuroprotective mechanisms are likely to be complex, several studies reported within the last few months were unable to reproduce the beneficial role of bexarotene in mouse models of Alzheimer’s disease.

    More research on novel RXR agonists is underway, with the goal of identifying a third generation of RXR agonists with higher potency and increased affinity for selective RXR/Nurr1 transactivation.

    View all comments by Giulio Pasinetti
  3. The studies reported with low-dose bexarotene are promising and consistent with findings in preclinical Parkinson's studies we have reported at various meetings using IRX4204, a more potent and selective RXR agonist than bexarotene. IRX4204 is a clinical-stage experimental compound. It has been well tolerated as a chronic treatment in Phase 2 clinical trials by patients with various cancers. We hope IRX4204 will be safe and effective for the treatment of PD. The use of RXR agonists to treat PD has a compelling biologic rationale. RXR agonists have the potential to alter the disease course of PD through their trophic effects on dopaminergic neurons, and may play an important role in the future therapy of PD.

    View all comments by Martin Sanders

References

News Citations

  1. Upping Brain ApoE, Drug Treats Alzheimer's Mice
  2. Bexarotene Revisited: Improves Mouse Memory But No Effect on Plaques

Paper Citations

  1. . Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease. ACS Chem Neurosci. 2013 Oct 11; PubMed.

External Citations

  1. PDGene
  2. Phase 2

Further Reading

Papers

  1. . Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener. 2013;8:18. PubMed.
  2. . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-d. PubMed.
  3. Parkinson disease: Transcription factor Nurr1 maintains dopaminergic neurons. Folia Neuropathol. 2012;50(4):322-9. PubMed.
  4. . Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease. ACS Chem Neurosci. 2013 Oct 11; PubMed.

Primary Papers

  1. . Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease. ACS Chem Neurosci. 2013 Oct 11; PubMed.